lnvasive aspergillosis of the nose and paranasal sinuses is one of the presentations of aspergillosis in granulocytopenic patients with neo- plastic disorders. It is most prevalent among patients with leukemia and granulocytopenia and is associated with a high mortality rate. We re- port five cases of invasive aspergillosis of the nose and paranasal si- nuses in profoundly neutropenic patients treated with broad spectrum antibiotics. Both Aspergillus fumigatus and Aspergillus f l a w s were cultured and identified in this entity. Awareness of this disease and early diagnosis made by culture and histologic examinations of biopsy material are essential. Treatment consisting of amphotericin B therapy and surgical debridement can be effective in eradicating this form of aspergillosis.

HEAD & NECK SURGERY 8~83-90 1985

ASPERGILLOSIS OF THE NOSE AND PARANASAL SINUSES IN NEUTROPENIC PATIENTS AT AN ONCOLOGY CENTER

ZVI LANDOY, MD, COLEMAN ROTSTEIN, MD, and DONALD SHEDD, MD

lnvasive aspergillosis has been reported with increasing frequency in recent years among cancerlP4 and other immunocompromised pa- t i e n t ~ . ~ - ~ It is the second most common fungal infection in patients with malignant disorder^.^'^ Aspergillus is ubiquitous in the en~i ronment ,~ and significant environmental exposure to Asper- gillus can lead to invasive disease in patients with neoplastic disorders." Invasion of lung parenchymal tissue and blood vessels follows col- onization of the tracheobronchial tree by inhaled Aspergillus spores in immunocompromised can- cer patients." Pulmonary involvement is present in almost all cases of invasive aspergillosis seen in this patient population.'y8

Although a variety of forms of invasive asper- gillosis are commonly seen in the lower respira- tory tract," Aspergillus rarely invades the upper respiratory tract in immunocompetent individ-

From the Departments of Laboratory Medicine (Dr Landoy), Medical Oncology (Dr Rotstein). and Head and Neck Surgery (Dr Shedd), Ros- well Park Memorial Institute, Buffalo, New York, and the Division of Infec- tious Diseases (Dr Rotstein) State University of New York at Buffalo, Buffalo, New York

Dr Landoy was supported by a scholarship from the American Physician Fellowship for Medicine in Israel

Address reprint requests to Dr Rotstein, Department of Medical Oncol- ogy, Roswell Park Memorial Institute. 666 Elm Street, Buffalo New York 14263

Accepted for publication May 10, 1985

01 48-6403108021083 $04 0018 1985 John Wiley & Sons, Inc

uals.12 Invasive aspergillosis of the nose and paranasal sinuses (IANPS) has been described in about 170 people (exclusive of the Sudan, where it is e n d e m i ~ ) , ~ " ~ - ~ ~ including 28 patients with m a l i g n a n ~ y . ~ . ~ ~ , ' ~ - ~ ~ Although it is not commonly seen in individuals with neoplastic diseases and neutropenia due to cytotoxic therapy, this form of aspergillosis is particularly serious, resulting in high m0rta1ity.l~ We report five patients with IANPS who were clustered in a 1-year period, de- scribe their diagnosis and treatment, and make some recommendations for the diagnosis, treat- ment, and possible prevention of this entity.

PATIENTS AND METHODS

Over a 1-year period, four patients with leukemia and one with aplastic anemia were hospitalized at Roswell Park Memorial Institute (RPMI). All pa- tients were profoundly neutropenic (< 100 neutro- phils/mm3). The patients with leukemia were ren- dered neutropenic by the administration of cytosine arabinoside (ara-C) with or without meta-"n4"-acridinyl amino-3-"methoxphenyl" methansulfuramide (m-AMSA) (three patients) or a bone marrow transplant conditioning regi- men of cyclophosphamide, ara-C, and total body irradiation (one patient). The patient with aplas- tic anemia received anti-thymocyte globulin (ATG) and large doses of prednisone (60 mg/day) as treatment for his disease.

Aspergillosis of the Nose and Paranasal Sinuses HEAD & NECK SURGERY NoviDec 1985 83

Each patient was followed by the Infectious Diseases and Head and Neck services of RPMI. Biopsies of nasal tissues were performed by the Head and Neck service on four of the five pa- tients. In these four cases, IANPS was defined as the presence of characteristic, acutely branching, septate hyphae invading mucosal tissue on patho- logic examination of hematoxylin and eosin, pe- riodic acid-Schiff, or methenamine silver stained mucosal biopsy material with or without the growth of Aspergillus sp. on Sabouraud dextrose agar or mycosel agar from the tissue biopsy mate- rial. The fifth case was defined as the presence of the typical clinical presentation of IANPS (erythema and swelling of the nasolabial fold, with facial and periorbital cellulitis, nasal drain- age, and involvement of the maxillary sinus) and the growth of Aspergillus from the nares and na- sal discharge.

Morphologic identification of Aspergillus was accomplished with lactophenol cotton blue stain- ing. Identification of the isolated Aspergillus or- ganisms was performed by the Division of Labo- ratories and Research of the New York State Department of Health, Albany, New York.

Autopsy findings were reviewed and cor- related with the clinical course of the disease whenever possible.

CASE REPORTS

Patient I. A 33-year-old man with recently diag- nosed aplastic anemia was transferred to RPMI for further therapy and consideration for bone marrow transplantation. The patient was treated with ATG 2 mg/kg/day for 7 days. Two weeks af- ter ATG therapy, serum sickness developed and prednisone 60 mg/day was administered. One week later the patient developed Pseudornonas aeruginosa perineal cellulitis with bacteremia. Piperacillin and tobramycin were initiated. His neutrophil count was <100/mm3 at this time.

During the sixth week of hospitalization, while his total white blood cell (WBC) count was 700/mm3 (100% lymphocytes), a red and tender swelling of the right nasolabial fold appeared (Figure 1). Culture of a nasal mucosa biopsy specimen grew A . flauus. Histologic examination of the biopsy revealed invading septate hyphae consistent with Aspergillus. Amphotericin B (1.2 mglkgiday) was given intravenously in combina- tion with rifampin (600 mg/day). Subsequently, swelling of the right side of his face increased. Nasal examination revealed destruction of the anterior portion of the right inferior turbinate. A

FIGURE 1. Patient with edema and erythema of the right nasolabial fold due to invasive aspergillosis of the nose and maxillary sinus.

computed tomographic (CT) scan of the nose and paranasal sinuses (which had been negative on the first day of clinical signs) showed a complete opacification of the right maxillary sinus (Figure 2). It was decided that drainage of the sinus was necessary, and an antrotomy (Caldwell-Luc pro- cedure) and an inferior turbinectomy were per- formed (Figure 3). The drains were left in his maxillary sinus through which irrigation of am- photericin B (amphotericin B 20 mg in 50 cc dex- trose and water twice a day) was performed. In- travenous amphotericin B 1.2 mg/kg/day was continued. An attempt to increase the amphoteri- cin B dosage to 1.5 mglkglday failed due to im- pairment of renal function. Gradual improvement in the edema and erythema of the right naso- labial fold and a marked decrease in the opacification of the right maxillary sinus ensued. The patient was discharged from the hospital 38 days after operation. The patient’s WBC count be- gan to rise 20 days postoperatively and peripheral WBC count at discharge was 1700/mm3, with 26% segmented forms, 2% monocytes, and 54% lym- phocytes. Amphotericin B was continued intrave-

84 Aspergillosis of the Nose and Paranasal Sinuses HEAD & NECK SURGERY NoviDec 1985

FIGURE 2. CT scan of patient with invasive aspergillosis of maxillary sinus demonstrating opacification of the right maxillary sinus.

FIGURE 3. Methenamine silver stain of the right inferior turbinate demonstrating tissue invasion by the branching septate hyphae of Aspergillus. (Magnification x 240).

Aspergillosis of the Nose and Paranasal Sinuses HEAD & NECK SURGERY NoviDec 1985 85

nously as an outpatient t o a total of 4 g. Ten months after discharge, the patient is left with a minimal oroantral fistula. There is no evidence of recurrence of IANPS.

Patient 2. A 36-year-old woman with a 12 year history of chronic myelogenous leukemia (CML) was found to be in blastic phase and was hos- pitalized for a bone marrow transplant. The pa- tient was conditioned with cyclophosphamide, ara-C, and total body irradiation. Four days after receiving an allogeneic bone marrow transplant, the patient developed a fever of 385°C. Car- benicillin and tobramycin were initiated. Seven days posttransplant, mucositis of her mouth de- veloped and acyclovir was added to her regimen because of herpetic stomatitis. One week later, with her total WBC count remaining at 100/mm3, the patient experienced a red and tender swelling of her left nasolabial fold, which progressed rap- idly and spread over the left maxillary area dur- ing the following days. X-ray films of her face and paranasal sinuses revealed only soft tissue in- volvement without bone destruction. Biopsy of the affected nasal area showed the typical acutely branching septate hyphae of Aspergillus invad- ing the mucosa. A. fumigatus grew from cultures of the biopsy specimen of the left nares. The pa- tient was treated with amphotericin B (1 mg/kg/ day) intravenously and rifampin (600 mg/day). Despite this treatment, a pulmonary infiltrate of the left lung appeared on chest x-ray and pro- gressed. Thoracotomy and partial lobectomy were performed to remove the infiltrate. The lung tis- sue also grew A. fumigatus. Postoperatively, the patient remained granulocytopenic and devel- oped bilateral pulmonary infiltrates. Granulocyte transfusions did not provide any benefit. Marked destruction of the left nasolabial fold due to As- pergillus also occurred. Her condition deterio- rated rapidly and she died of respiratory failure. No autopsy was performed.

Patient 3. A 69-year-old woman with recently diagnosed acute myelomonocytic leukemia (AMML) was admitted to RPMI for chemother- apy. The patient sustained an acute myocardial infarction on admission, which necessitated a de- lay in the initiation of chemotherapy. Twelve days after the administration of high dose ara-C (2 g/m2 q 12 hours for 6 days) followed by m- AMSA (100 mg/m2 for 3 days), the patient experi- enced left nasolabial swelling with an erythema- tous and tender area in the left paranasal area.

She was being treated with carbenicillin and to- bramycin at the time, and her WBC was <loo/ mm3. Sinus x-ray films showed opacification of the left maxillary sinus without bone destruction. Biopsy of the involved necrotic nasal area was consistent with invasive aspergillosis on his- tologic examination (Figure 4). Fungal cultures were negative. The patient continued to be neu- tropenic and was treated with amphotericin B (0.8 mgikglday) and rifampin (600 mg/day), but developed acute renal failure. Her general condi- tion deteriorated and she died of acute renal fail- ure and congestive heart failure. Necroscopic findings demonstrated aspergillosis of the lungs, trachea, nose, and paranasal sinuses, and A. fumigatus was cultured from the left nostril.

Patient 4. A 38-year-old woman with a diagnosis of acute myelogenous leukemia (AML) was trans- ferred to RPMI for further chemotherapy. One week after ara-C treatment was completed, with her WBC count remaining 100/mm3, periorbital cellulitis with conjunctivitis and proptosis of the left eye, nasal discharge, and left nasolabial fold swelling developed. A CT scan of the orbit showed a left intraorbital mass extending to the nasal vault. The mucosa of the left maxillary sinus was edematous, but no bone destruction was noted. Cultures of the left nares and nasal discharge grew A. fumigatus. The patient was treated with amphotericin B (dosage 0.6 mgikglday) intrave- nously, but she was persistently neutropenic. Her condition declined rapidly, and she developed bi- lateral pneumonia. At autopsy, Aspergillus pneu- monia and tracheitis were found. A. fumigatus was grown from lung tissue.

Patient 5. A 53-year-old man with AML was ad- mitted to RPMI for chemotherapy. Three weeks after receiving m-AMSA 120 mg/m2 for 5 days, the patient’s WBC count was 600/mm3. An epi- sode of fever, chills, epistaxis, and swelling with tenderness and erythema of the right side of the face developed. X-ray films and CT scan of the sinuses were normal. Broad spectrum antibiotic treatment was initiated. One week later, while continuing to be neutropenic, a black plaque was noted on the right side of the nasal septum. A biopsy of the nasal septum area was consistent with aspergillosis, but the fungal culture was negative. The patient was treated with am- photericin B (dosage 0.6 mg/kg/day) intrave- nously and was scheduled for surgery. On the day of surgery, the patient expelled the black plaque

86 Aspergillosis of the Nose and Paranasal Sinuses HEAD & NECK SURGERY NoviDec 1985

FIGURE 4. Necrotic tissue from the wall of the left nostril of patient 3 invaded by the branching septate hyphae of Aspergillus. (Hernatoxylin and eosin stain, magnification x 240.)

with a large sneeze. He was left with a large per- foration of the septum, but the margins were negative for Aspergillus on biopsy. He continued to receive amphotericin B to a total of 752 mg, over 2Y2 weeks. His WBC rose to 3000/mm3; how- ever, he was in relapse, with bone marrow con- taining 50% blasts. The patient subsequently died of Klebsiella oxytoca bacteremia, but no evi- dence of IANPS was found at autopsy.

RESULTS

Between January 1983 and December 1983, five patients with IANPS were seen at our institution (Table 1). Four patients were located in one par- ticular nursing unit in different hospital rooms, while the other patient (patient 2) developed her disease on another nursing unit in a different building in the institution. The female-to-male ratio was 3:2.

All patients were profoundly neutropenic (neutrophil count <100/mm3) at the time of onset of IANPS and all patients were treated with broad spectrum antibiotics for 23 weeks before onset of aspergillosis. In all five patients nasal or facial swelling was the first clinical sign of IANPS (Figure 1). Physical examination of the nasal mucosa revealed ulcerated lesions in four patients. Destruction of the inferior turbinate was observed in one and septa1 perforation in an-

other. Biopsy of these lesions demonstrated the histologic characteristics of tissue invasion by Aspergillus. Culture of the biopsy specimen was positive in only two of the patients. A . f laws and A . fumigatus were isolated, respectively. In one case (patient 4), no histologic evidence of the diag- nosis was sought, but the presence of A . fumigatus on nasal culture with the typical clini- cal presentation was believed to be sufficient to confirm the diagnosis. Sinus opacification was present on plain x-ray films in three cases and on CT scan of the area (Figure 2) in three instances. An interval of 3-10 days occurred from the onset of symptoms to diagnosis and therapy in all cases.

Treatment with amphotericin B at a dosage of 0.6-1.2 mg/kg/day was administered intrave- nously to all patients. Rifampin 600 mg/day was added in three cases (patients 1,2, and 3) for vari- able periods of time (3-10 days) with no demon- strable benefit. Surgery (Caldwell-Luc procedure) was performed in only one patient for nasal and maxillary sinus aspergillosis. Postoperatively, this patient received amphotericin B irrigations of the nose and maxillary sinus (amphotericin B 20 mg in 50 cc dextrose and water twice a day) in addition to amphotericin B intravenously. This patient was the only survivor. It is of note that his absolute neutrophil count rose to >200/mm3 after 3 weeks of treatment and was 442/mm3 at the

Aspergillosis of the Nose and Paranasal Sinuses HEAD & NECK SURGERY Nov/Dec 1985 87

Table 1. Cases of invasive aspergillosis of the nose and paranasal sinuses

Patient number

1 2 3 4 5

Diagnosis Aplastic anemia CML, blastic crisis; bone marrow transplant

33 36 M F + +

Acute My- elomonocytic Leu kem ia

69 F +

Acute Myeloge- nous leukemia

Acute myelogenous leu kem ia

Age (years) Sex Neutropenia while

Cytotoxic drugs infected

38 F +

53 M +

+ + , total body irradi- ation

+ Left side of face,

destruction of left nasolabial fold

No sinus involve- ment, lung in- volvement

Nose and lung A fumigatus

4 + +

Steroids Soft tissue involve-

ment

+ Right side of face;

destruction of tur- binate bone

Maxillary sinus opacification

-

Right side of face; necrosis nasal septum

No sinus involve- ment

Left nares Periorbital cellulitis; proptosis

X-ray findings Left maxillary sinus opacification; no bone destruction

Nose negative

Orbital and maxil- lary sinus inva- sion

Nose and nasal discharge A. fumigatus

Note done

Cultures Nose A. f laws Nose Negative

Histologic diag- nosis

Broad spectrum an- tibiotics

Antifungal treat- ment

Outcome

+ t + +

+ t + + +

Amphotericin 6 Amphotericin B and rifampin and rifampin

Alive Died, Aspergdlus pneumonia

Amphotericin and rifampin

Died; congestive heart failure; As- pergillus pneu- monia

Aspergillus of lungs, trachea, nose, and paranasal si- nuses; A. fumigatus from left nostril

Amphotericin 6 AmDhotericin B

Died; Aspergillus pneumonia

Died; K. oxytoca sepsis

Autopsy findings Survivor Not done Aspergillus pneu- monia; A. fumigatus cul- tured from lung

Diffuse leukemic infiltration of lung, no evidence of aspergillosis

+ = Present. - = Not used

time of discharge. The other patients were judged to be poor surgical candidates because of concur- rent pulmonary problems. Three patients died of pulmonary involvement with aspergillosis, which appeared to develop after the onset of IANPS, and one patient with IANPS succumbed t o gram- negative sepsis. In none of the latter four cases did neutrophil counts rise above 200/mm3.

congestion, and discharge, symptoms that mimic sinusitis but do not improve with antibiotic ther- apy. The diagnosis is made by biopsy, and com- plete surgical removal of the offending organism from the paranasal sinuses is the treatment of c h o i ~ e . ' ~ - ~ ~

The second presentation is invasive aspergil- losis of the nose and paranasal sinuses. It is char- acterized by invasion and destruction of the bony sinus walls, the orbit, and other soft tissues of the f a ~ e , ~ ' , ~ ' although the clinical presentation may be subtle. This form is seen in immunocompetent and immunocompromised individuals. "-" In particular, it has been described in patients with leukemic malignancies.'8-2'~23 Alth ough the mor-

DISCUSSION

Aspergillosis of the nose and paranasal sinuses is a relatively uncommon disease in healthy indi- viduals exclusive of the Sudan." It may present in two distinct forms. The first is a benign or indo- lent form. Patients complain of stuffiness, nasal

88 Aspergillosis of the Nose and Paranasal Sinuses HEAD & NECK SURGERY NoviDec 1985

tality rate in normal individuals is =16%," it ap- proaches 80% in immunocompromised cancer pa- tients" (present series). It is clear that IANPS can be a devastating disease in this population and may be the initial site of aspergillosis, lead- ing to the development of pulmonary or dis- seminated a s p e r g i l l ~ s i s . ~ ~ ~ ~ ~ ~ ~ ~ ~ ~

Some authors have emphasized that host risk factors such as granul~cytopenia,~,~ corticoste- roids,'s5 and antibiotic therapyz5 act as predispos- ing factors to aspergillosis. It is believed that the major host defense against Aspergillus infection is the n e u t r ~ p h i l . ~ ~ ~ ~ ~ Prolonged granulocytopenia has been identified as the major risk factor for invasive pulmonary aspergillosis in patients with acute leukemia in a controlled trial.3 In our series of patients with IANPS, all patients had profound neutropenia and received broad spectrum antibi- otics, and two patients were treated with cortico- steroids, but no controlled analysis of these fac- tors was performed.

The spores of the ubiquitous Aspergillus, when inhaled, reach the mucous membranes of the nose and paranasal sinuses. The organism merely colonizes the upper respiratory tract in immunocompetent hosts; however, it can, under certain conditions, produce benign or invasive as- pergillosis of the nose and paranasal sinuses, as mentioned above. Yet, in the granulocytopenic immunocompromised host, Aspergillus behaves quite differently. In these circumstances, it is highly pathogenic and readily invades due to the lack of neutrophil host defenses (a characteristic common to other nonpathogenic organisms that colonize neutropenic hosts). Aisner et al.25 have suggested that the presence of A . flavus or A . fumigatus on nose culture is predictive for subse- quent or concurrent invasive aspergillosis of the lung or maxillary sinuses in acute leukemia pa- tients. They also demonstrated that leukemic pa- tients with A . flavus on nose culture had small ulcerating lesions high on the nasal septum which, when scraped, showed the typical branch- ing septated hyphae of Aspergillus found on smears.25 We also believe that the presence ofAs- pergillus sp. on culture or nasal scrapings in pro- foundly granulocytopenic patients represents the nasal invasion of IANPS, not only a good predic- tor of subsequent or concurrent disease. Perhaps nasal invasion in granulocytopenic hosts is the initial portal of entry for some cases of aspergil- 1 0 s i s , ~ ~ , ~ ~ preceding pulmonary andor dissem- inated aspergillosis, which cause high mortal- ity in these hosts. It is of interest that we found that A. fumigatus had as much of a predilection

for the upper airways as A . flauus, although Ais- ner and co-workersZ5 found A . flauus predomi- nating in nasal cultures.

Early diagnosis and treatment are imperative in granulocytopenic patients with malignancy. Positive surveillance cultures of the nose for As- pergillus in profoundly granulocytopenic patients can alert the physician to the presence of IANPS. Regular examinations of the nasal cavity with scrapings of suspicious lesions for culture and his- tology can detect the ulcerating lesions of inva- sive aspergillosis of the nose. Also, early recogni- tion of the subtle signs and symptoms of IANPS, which may be limited due to the paucity of white cell inflammatory response, will prompt the phy- sician to obtain biopsies and culture suspicious lesions. Once the diagnosis of IANPS is proven, both surgical intervention and intravenous anti- fungal therapy with amphotericin B should be employed. Surgical debridement (a Caldwell-Luc for maxillary sinus involvement, an external eth- moidectomy and sphenoidotomy for ethmoid sinus involvement, a frontoethmoidectomy for frontal sinus involvement, a resection of quadrangular cartilage and vomer for nasal septum involve- ment, the removal of necrotic turbinates for turbi- nate involvement, and a debridement of the soft tissue of the nose when it is involvedz4), with ad- junctive platelet transfusions to ensure adequate hemostasis, can remove necrotic infected tissue from the nose or sinuses, allowing better penetra- tion of antifungal therapy into the infected area." Yet, such surgery may be inapplicable due to other serious underlying medical problems of these patients. Amphotericin B irrigations of the nose and paranasal sinuses as an adjunct to sys- temic amphotericin B therapy may aid in eradicating the fungus and assist in the evacua- tion of oozing blood to prevent clot formation. The addition of rifampin to amphotericin B may prove to be beneficial," but requires further study in profoundly granulocytopenic patients with malig- nancy.

At present, the detection of Aspergillus anti- body is not very helpful in immunocompromised hosts for the diagnosis of invasive aspergillosis but radioimmunoassay of Aspergillus antigen looks promising.30

Very little clinical investigation has been per- formed in an effort to prevent aspergillosis in granulocytopenic patients with malignant disor- ders. Recently, the prophylactic use of a prepared amphotericin B nasal spray delivered by an atomizer in granulocytopenic patients with can- cer has been shown to be somewhat effective in

Aspergillosis of the Nose and Paranasal Sinuses HEAD & NECK SURGERY Nov/Dec 1985 89

reducing colonization (invasion) of the nose and the incidence of invasive pulmonary aspergil- 10sis.~’ The use of HEPA filtered rooms, i.e., a protected environment, has been noted to de- crease the incidence of invasive aspergillosis among bone marrow transplant recipient^.^^ It would seem that a combination of fungal chemo- prophylaxis and protected environments may be the most effective means of preventing IANPS in granulocytopenic hosts.

IANPS is a devastating disease in granulocy-

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90 Aspergillosis of the Nose and Paranasal Sinuses HEAD & NECK SURGERY NoviDec 1985